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Epigenetic regulation of exhausted CD8 T cells via the miR-29a-TET2 axis

Award Number: R01AI183292
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/21/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Epigenetic regulation of exhausted CD8 T cells via the miR-29a-TET2 axis - Chronic infections and cancer cause CD8 T cell exhaustion, a differentiation state characterized by the inability of CD8 T cells to provide immunological protection. Improving the function of exhausted T cells (TEX) by antagonizing checkpoint inhibitors is a potent immunotherapeutic strategy. However, most patients do not exhibit long-term protection, creating a need for improved immunotherapeutic strategies. Resistance to immunotherapy is mainly attributed to the inability of checkpoint inhibitors to reverse the TEX epigenome. Therefore, epigenetically re-directing TEX differentiation to induce durable responses is key to overcoming resistance to immunotherapy. To date, modifying a single transcriptional pathway has had limited success in providing full TEX reinvigoration and inducing long-term persisting immune responses. Instead, microRNAs (miRs) can have a profound impact on the epigenetic regulation of immune cells; however, the role of miRs in TEX differentiation is understudied. We recently identified miR-29a as a unique memory-associated miR that is repressed in TEX. We demonstrated that ectopic expression of miR-29a enhances TEX persistence, attenuates their exhaustion, and promotes differentiation of a TEX subset with progenitor, stem-like characteristics that responds to immunotherapy. Importantly, our preliminary data suggest that miR-29a alters the epigenetic profile of TEX and promotes durable CD8 T cell responses, in striking contrast to anti-PD-L1 therapy. Mechanistically, we demonstrate that miR-29a directly targets the key DNA demethylating enzyme TET2 and that TET2 overexpression abrogates key effects of miR-29a in TEX differentiation. However, the molecular circuits involving miR-29a and TET2 and the implication of miR-29a-TET2 axis in checkpoint inhibitor therapy is unknown. The goal of this proposal is to uncover the role of miR-29a in targeting the key epigenetic modulator TET2 and, thus, define the role of miR-29a in synergizing with checkpoint inhibitors. Our central hypothesis is that miR-29a regulates DNA methylation by directly targeting TET2, therefore, synergizes with checkpoint inhibitors to re-direct TEX differentiation. Aim 1. Identify the role of the miR-29a-TET2 axis in regulating TEX differentiation. We hypothesize that miR- 29a regulates DNA demethylation, by directly targeting TET2, thereby fundamentally alters TEX differentiation. We will elucidate the TET2-dependent versus TET2-independent effects of miR-29a in TEX differentiation and the downstream effects in DNA methylation. Aim 2. Identify the pathways by which miR-29a synergizes with anti-PD-L1. We hypothesize that miR-29a epigenetically alters the differentiation of the progenitor TEX subset and, thereby, synergizes with anti-PD-L1 to promote durable TEX reinvigoration. We will elucidate the molecular mechanisms of synergy between miR-29a and anti-PD-L1 and we will define the TET2-dependent and TET2-independent roles of miR-29a in synergizing with anti-PD-L1 in mouse models of LCMV and B16 melanoma.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $585,074 )
2026	2026	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Allergy and Infectious Diseases Research	000	3	4/29/2026	NON-COMPETING CONTINUATION	$585,074
														Subtotal = $585,074

Issue Date FY: 2025 ( Subtotal = $451,004 )
2025	2025	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Allergy and Infectious Diseases Research	000	2	4/29/2025	NON-COMPETING CONTINUATION	$451,004
														Subtotal = $451,004

Issue Date FY: 2024 ( Subtotal = $425,216 )
2024	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Allergy and Infectious Diseases Research	000	1	6/21/2024	NEW	$382,694
2024	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Allergy and Infectious Diseases Research	001	1	9/3/2024	NEW	$42,522
														Subtotal = $425,216

Grand Total All Awards = $1,461,294

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Epigenetic regulation of exhausted CD8 T cells via the miR-29a-TET2 axis

Award Number: R01AI183292

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/21/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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